14 CLINICAL STUDIES

14.1 Chronic Sialorrhea

Chronic Sialorrhea in Adult Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in adult patients were evaluated in a double-blind, placebo-controlled clinical trial (NCT02091739) that enrolled a total of 184 patients with chronic sialorrhea resulting from Parkinson's disease, atypical parkinsonism, stroke, or traumatic brain injury, that was present for at least three months. Patients with a history of aspiration pneumonia, amyotrophic lateral sclerosis, salivary gland or duct malformation, and gastroesophageal reflux disease were excluded. The study consisted of a 16-week main phase, followed by an extension period of dose-blinded treatment with XEOMIN.

In the main phase, a fixed total dose of XEOMIN (100 Units or 75 Units) or placebo was administered into the parotid and submandibular salivary glands in a 3:2 dose ratio. The co-primary efficacy variables were the change in unstimulated Salivary Flow Rate (uSFR, Table 15) and the change in Global Impression of Change Scale (GICS, Table 16) at Week 4 post-injection. A total of 173 treated patients completed the main phase of the study. For both the uSFR and GICS, XEOMIN 100 Units was significantly better than placebo (see Table 15 and Table 16). XEOMIN 75 Units was not significantly better than placebo.

Table 15: Mean Change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase
	XEOMIN 100 Units	Placebo
	N=73	N=36
* p=0.004
Week 4*	-0.13	-0.04
Week 8	-0.13	-0.02
Week 12	-0.12	-0.03
Week 16	-0.11	-0.01

Table 16: Mean GICS at Week 4, 8, 12, and 16 of Main Phase
	XEOMIN 100 Units	Placebo
	N=74	N=36
* p=0.002
Week 4*	1.25	0.67
Week 8	1.30	0.47
Week 12	1.21	0.56
Week 16	0.93	0.41

In the extension period, patients received up to three additional treatments with XEOMIN 100 Units or 75 Units every 16±2 weeks, for a total exposure duration of up to 64 weeks. Patients had periodic dental examinations to monitor for changes in dentition and oral mucosa. A total of 151 patients completed the extension period.

Chronic Sialorrhea in Pediatric Patients

The efficacy and safety of XEOMIN for the treatment of chronic sialorrhea in pediatric patients were evaluated in a prospective, randomized, double-blind, placebo-controlled (ages 6-17 years), parallel-group, multicenter trial (NCT02270736) that enrolled and treated a total of 216 pediatric patients 6-17 years of age with chronic sialorrhea associated with cerebral palsy, other genetic or congenital disorders, or traumatic brain injury. An additional 35 patients 2-5 years of age were treated with open-label XEOMIN in that study. The study consisted of a 16-week main phase, followed by an open-label extension period of treatment with XEOMIN where patients could receive up to 3 additional treatments with XEOMIN every 16 ± 2 weeks, for a total exposure duration of up to 64 weeks (222 patients completed the extension period).

In the main phase, patients 6-17 years of age were administered a total dose of XEOMIN according to body weight (up to 75 Units), or placebo, into the parotid and submandibular glands in a 3:2 dose ratio, using ultrasound guidance. Patients 2-5 years of age all received open-label treatment with XEOMIN, according to body weight, using ultrasound guidance. Patients with a body weight <12 kg were excluded.

The primary efficacy analysis was conducted in the 6-17 years of age patient group. The co-primary endpoints were the change in unstimulated Salivary Flow Rate (uSFR, Table 17) and carer's Global Impression of Change Scale (GICS, Table 18) at Week 4 post-injection.

For both the uSFR and GICS, XEOMIN was statistically significantly better than placebo (see Table 17 and Table 18).

Table 17: Mean change in uSFR (g/min) from Baseline at Week 4, 8, 12, and 16 of Main Phase
	XEOMIN (6-17 years) N = 148	Placebo (6-17 years) N=72
* p=0.0012
Week 4*	-0.14	-0.07
Week 8	-0.16	-0.07
Week 12	-0.16	-0.06
Week 16	-0.15	-0.08

Table 18: Mean carer's GICS at Week 4, 8, 12, and 16 of Main Phase
	XEOMIN (6-17 years) N = 148	Placebo (6-17 years) N=72
* p=0.0320
Week 4*	0.91	0.63
Week 8	0.94	0.54
Week 12	0.87	0.47
Week 16	0.77	0.38

Efficacy in pediatric patients 2 to 5 years of age is extrapolated from the finding of efficacy in older pediatric patients.

14.2 Upper Limb Spasticity

Upper Limb Spasticity in Adult Patients

The efficacy and safety of XEOMIN for the treatment of upper limb spasticity in adult patients were evaluated in two Phase 3, randomized, multi-center, double-blind studies.

Study 1 (NCT01392300) and Study 2 (NCT00432666) were both prospective, double-blind, placebo-controlled, randomized, multi-center trials with an open-label extension period (OLEX) to investigate the efficacy and safety of XEOMIN in the treatment of post-stroke spasticity of the upper limb. For patients who had previously received botulinum toxin treatment in any body region, Study 1 and Study 2 required that ≥12 months and ≥4 months, respectively, had passed since the most recent botulinum toxin administration.

Study 1 consisted of a 12-week main phase followed by three 12-week OLEX treatment cycles for a total exposure duration of 48 weeks. The study included 317 treatment-naïve patients who were at least three months post-stroke in the main study period (210 XEOMIN and 107 placebo). During the main period, XEOMIN (fixed total dose of 400 Units) and placebo were administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups. 296 treated patients completed the main phase and participated in the first OLEX cycle. Each OLEX cycle consisted of a single treatment session (XEOMIN 400 Units total dose, distributed among all affected muscles) followed by a 12-week observation period.

Study 2 consisted of a 12-to-20-week main phase followed by an OLEX period of 48 – 69 weeks, for up to 89 weeks of exposure to XEOMIN. The study included 148 treatment-naïve and pre-treated patients with a confirmed diagnosis of post-stroke spasticity of the upper limb who were at least six months post-stroke (73 XEOMIN and 75 placebo). During the main period, for each patient, the clinical patterns of flexed wrist and clenched fist were treated with fixed doses (90 Units and 80 Units, respectively). Additionally, if other upper limb spasticity patterns were present, the elbow, forearm and thumb muscles could be treated with fixed doses of XEOMIN per muscle. 145 patients completed the main phase and participated in the OLEX period, during which time the dosing of each involved muscle could be adapted individually. During the main and OLEX periods, the maximum total dose per treatment session and 12-week interval was 400 Units.

The average XEOMIN doses injected into specific muscles and the number of injection sites per muscle in Study 1 and Study 2 are presented in Table 19.

Table 19: Doses Administered to Individual Muscles (Main Period) in Adult Upper Limb Spasticity Study 1 and Study 2 Intent to Treat (ITT)
Muscle Group	Muscle	Study 1 Units Injected	Injection Site Per Muscle	Study 2 Units Injected	Injection Site Per Muscle
		XEOMIN (N=210) Mean±SD	XEOMIN Median (Min; Max)	XEOMIN (N=73) Mean±SD	XEOMIN Median (Min; Max)
All	Overall	400 ± 2 Units	--	307 ± 77 Units	--
Elbow flexors	Overall	151 ± 50 Units	5 (1; 11)	142 ± 30 Units	5 (2; 9)
	Biceps	90 ± 21 Units	3 (1; 4)	80 ± 0 Units	3 (2; 4)
	Brachialis	52 ± 26 Units	2 (1; 4)	50 ± 0 Units	2 (1; 2)
	Brachioradialis	43 ± 16 Units	2 (1; 3)	60 ± 2Units	2 (1; 3)
Wrist flexors	Overall	112 ± 43 Units	4 (1; 6)	90 ± 0 Units	4 (4; 4)
	Flexor carpi radialis	58 ± 22 Units	2 (1; 3)	50 ± 0 Units	2 (2; 2)
	Flexor carpi ulnaris	56 ± 22 Units	2 (1; 3)	40 ± 0 Units	2 (2; 2)
Finger flexors	Overall	104 ± 35 Units	4 (1; 4)	80 ± 0 Units	4 (4; 4)
	Flexor digitorum profundus	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
	Flexor digitorum superficialis	54 ± 19 Units	2 (1; 2)	40 ± 0 Units	2 (2; 2)
Forearm pronators	Overall	52 ± 24 Units	2 (1; 3)	47 ± 16 Units	2 (1; 3)
	Pronator quadratus	26 ± 13 Units	1 (1; 1)	25 ± 0 Units	1 (1; 1)
	Pronator teres	42 ± 13 Units	1 (1; 2)	40 ± 0 Units	1.5 (1; 2)
Thumb flexors/ adductors	Overall	37 ± 25 Units	2 (1; 4)	25 ± 10 Units	1.5 (1; 3)
	Adductor pollicis	14 ± 8 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis brevis / opponens pollicis	14 ± 9 Units	1 (1; 1)	10 ± 0 Units	1 (1; 1)
	Flexor pollicis longus	26 ± 16 Units	1 (1; 2)	20 ± 0 Units	1 (1; 1)

In Study 1, the primary efficacy variable was the change from baseline in Ashworth Scale (AS) score of the primary target clinical pattern determined by the investigator at the Week 4 visit. The Ashworth Scale is a clinical measure of the severity of spasticity by judging resistance to passive movement. The spasticity of the elbow flexors, wrist flexors, finger flexors, and thumb muscles as well as the forearm pronators was assessed on the 0 to 4-point Ashworth scale at each visit. The co-primary efficacy variable of Study 1 was the Investigator's Global Impression of Change Scales (GICS) after 4 Weeks of treatment with XEOMIN or placebo. The GICS is a global measure of a subject's functional improvement. Investigators were asked to evaluate the subject's global change in spasticity of the upper limb due to treatment, compared to the condition before the last injection. The response was assessed using a 7-point Likert scale that ranges from –3 (very much worse) to +3 (very much improved). XEOMIN was considered to be superior to placebo in Study 1 only if statistical significance was reached in both the AS and GICS variables.

The primary efficacy results are displayed in Table 20.

Table 20: Efficacy Results by Patterns of Spasticity in Adult Upper Limb Spasticity Study 1, Week 4
	Mean Change in Ashworth Scale
	XEOMIN (N=171)	Placebo (N=88)
The analysis is based on Last Observation Carried Forward in the Intent To Treat population. p<0.001
Total Primary Target Clinical Pattern (flexed wrist, flexed elbow, and clenched fist)	-0.9	-0.5

A greater percentage of XEOMIN-treated subjects (43%) than placebo-treated subjects (23%) reported 'very much improved' and 'much improved' in their spasticity (see Figure 8).

Figure 8: Investigator's GICS in Adult Upper Limb Spasticity Study 1

Upper Limb Spasticity in Pediatric Patients

Study 1 (NCT02002884) was a prospective, double-blind, dose-response, randomized, multi-center trial with an open-label extension period to evaluate the efficacy and safety of XEOMIN for the treatment of upper limb spasticity in pediatric patients. Study 1 enrolled a total of 350 pediatric patients 2 to 17 years of age with upper limb spasticity in one or both upper limbs. In the double-blind main period of Study 1, patients were randomized to one of three dosages of XEOMIN: 2 Units/kg (maximum 50 Units per upper limb), 6 Units/kg (maximum 150 Units per upper limb); or 8 Units/kg (maximum 200 Units per upper limb). The maximum dose, if both upper limbs were treated, respectively was 4 Units/kg (maximum 100 Units), 12 Units/kg (maximum 300 Units), or 16 Units/kg (maximum 400 Units). For treatment of flexed elbow, injection of biceps brachii was mandatory. The investigator could select 1 of the 2 other muscles contributing to spasticity of elbow flexion (i.e., brachialis and brachioradialis) for injection. For patients needing treatment for a flexed wrist, both the flexor carpi radialis and flexor carpi ulnaris were injected. Study 1 used a dose-response design, in which the two highest dosages of XEOMIN (8 Units/kg and 6 Units/kg) were compared to the lowest dosage (2 Units/kg), which served as control. In the absence of a placebo control, the efficacy of the 2 Units/kg dosage of XEOMIN could not be evaluated in Study 1.

The co-primary efficacy variables in Study 1 were the change from baseline on the Ashworth Scale for the primary clinical target pattern (i.e., elbow flexors or wrist flexors), and the Investigator's Global Impression of Change Scale (GICS), both at Week 4. The GICS is a global measure of a subject's functional improvement based on a 7-point Likert scale that ranges from -3 = very much worse to +3 = very much improved.

As displayed in Table 21, the change from baseline in Ashworth Scale score was significantly greater for patients treated with XEOMIN 8 Units/kg than for patients treated with XEOMIN 2 Units/kg. The difference in GICS score between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg did not reach statistical significance. However, the clinical meaningfulness of the difference in Ashworth Scale score change between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg was established by a responder analysis, in which the proportion of patients with a 1-point change or greater on the Ashworth Scale was examined. In that analysis, 86% of patients treated with XEOMIN 8 Units/kg met the responder definition, compared to 71% of patients treated with XEOMIN 2 Units/kg (nominal p value = 0.0099).

There was no significant difference in change from baseline in Ashworth Scale score, GICS score, or proportion of responders between patients treated with XEOMIN 6 Units/kg and those treated with XEOMIN 2 Units/kg. Therefore, the efficacy of a 6 Units/kg dosage of XEOMIN for the treatment of upper limb spasticity in pediatric patients was not established in Study 1.

Table 21: Ashworth Scale and GICS Efficacy Results in Pediatric Upper Limb Spasticity Study 1, Week 4
	XEOMIN 2 Units/kg (N=87)	XEOMIN 8 Units/kg (N=176)
LS = Least Square Mean difference
CI = Confidence Interval
* p-value versus low dose group <0.05
Ashworth Scale
Mean Change from Baseline at Week 4	-0.9	-1.2
LS Mean Difference versus XEOMIN 2 Units/kg (95% CIs)	--	-0.22* (-0.40, -0.04)
GICS
Mean at Week 4	1.6	1.7
LS Mean Difference versus XEOMIN 2 Units/kg (95% CIs)	--	0.09 (-0.10, 0.28)

14.3 Cervical Dystonia

XEOMIN has been investigated in a randomized, double-blind, placebo-controlled, multicenter trial (NCT00407030) in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥20, TWSTRS severity score ≥10, TWSTRS disability score ≥3, and TWSTRS pain score ≥1. For patients who had previously received a botulinum toxin treatment for cervical dystonia, the trial required that ≥10 weeks had passed since the most recent botulinum toxin administration. Patients with swallowing disorders or any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (1:1:1) to receive a single administration of XEOMIN 240 Units (n=81), XEOMIN 120 Units (n=78), or placebo (n=74). Each patient received a single administration of 4.8 mL of reconstituted study agent (XEOMIN 240 Units, XEOMIN 120 Units, or placebo). The investigator at each site decided which muscles would receive injections of the study agent, the number of injection sites, and the volume at each site. The muscles most frequently injected were the splenius capitis/semispinalis, trapezius, sternocleidomastoid, scalene, and levator scapulae muscles. Table 22 indicates the average XEOMIN dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trial.

Table 22: XEOMIN 120 Units Initial Dose (Units and % of the Total Dose) by Unilateral Muscle Injected During Double Blind Pivotal Phase 3 Study
		XEOMIN Dose Injected
	Number of Patients Injected Per Muscle	Median XEOMIN Units	75th percentile XEOMIN Units
Sternocleidomastoid	63	25	35
Splenius capitis/ Semispinalis capitis	78	48	63
Trapezius	55	25	38
Levator scapulae	49	25	25
Scalenus (medius and anterior)	27	20	25

Most patients received a total of 2-10 injections into the selected muscles. Patients were assessed by telephone at one week post-injection, during clinic visits at Weeks 4 and 8, and then by telephone assessments or clinic visits every two weeks up to Week 20.

The mean age of the study patients was 53 years, 66% of the patients were women, and 91% were White. At study baseline, 61% of patients had previously received a botulinum toxin as treatment for cervical dystonia. The study was completed by 94% of study patients. Three patients discontinued the study prematurely due to adverse events: two patients in the 240 Unit group experienced musculoskeletal pain and muscle weakness, and one patient in the 120 Unit group experienced nausea and dizziness.

The primary efficacy endpoint was the change in the TWSTRS total score from baseline to Week 4 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's baseline value. TWSTRS evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain, with a range of possible scores from 0 to 85. The mean change in the total TWSTRS score was significantly greater for both XEOMIN groups than for the placebo group (Table 23).

Table 23: Change in TWSTRS Score at Week 4 in Patients with Cervical Dystonia (Double Blind Pivotal Phase 3 Study)
TWSTRS Assessment	XEOMIN 240 Units (N=78)	XEOMIN 120 Units (N=81)	Placebo (N =74)
SD = Standard Deviation, CI = Confidence Interval.
* p-value(s) are from ANCOVA model.
Total TWSTRS at baseline	42.1	42.6	41.8
Total TWSTRS at Week 4	31.2	32.7	39.5
Mean (SD) Change in TWSTRS score from baseline to Week 4	-10.9 (11.7)	-9.9 (10.4)	-2.2 (7.3)
Mean difference from placebo (95% CI)	-9.0 (-12.0, -5.9)	-7.5 (-10.4, -4.6)
p-value* versus placebo	<0.001	<0.001

The efficacy of XEOMIN was similar in patients who were botulinum toxin naïve and those who had received botulinum toxin prior to this study.

Examination of age and gender subgroups did not identify differences in response to XEOMIN among these subgroups.

14.4 Blepharospasm

Treatment-Naïve Patients

The efficacy and safety of XEOMIN for the treatment of blepharospasm in treatment-naïve patients were evaluated in Study 1 (NCT01896895), a randomized, double-blind, placebo-controlled, multi-center trial in a total of 61 patients. Patients had a clinical diagnosis of blepharospasm, with a baseline Jankovic Rating Scale (JRS) severity subscore ≥2. Patients were defined as treatment-naïve if at least 12 months had passed since their last botulinum toxin treatment for blepharospasm. During the placebo-controlled phase, a fixed total dose of 25 Units XEOMIN (n=22), 50 Units XEOMIN (n=19), or placebo (n=20) was administered intramuscularly at 6 injection sites per eye (Figure 9). Of the 61 patients randomized, 55 patients completed the placebo-controlled phase. Patients only continued to the open-label extension (OLEX) period if they had a confirmed need for a re-injection by week 20 of the placebo-controlled phase. A total of 39 patients entered and completed the OLEX phase.

The primary efficacy variable was the change from baseline in JRS Severity subscore determined at Week 6 after the injection. The 50 Unit treatment group demonstrated statistically significant improvements compared to placebo, with a difference of -1.2 (p=0.0004). The change from baseline in the JRS Severity subscore for the 25 Unit treatment group 6 weeks after the injection was not statistically significant, with a difference of -0.5 (p=0.1452) compared to placebo (see Figure 9).

Figure 9: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6 for Treatment-Naïve Patients

Pre-Treated Patients

The efficacy and safety of XEOMIN for the treatment of blepharospasm patients pre-treated with onabotulinumtoxinA (Botox) were evaluated in Study 2 (NCT00406367), a randomized, double-blind, placebo-controlled, multi-center trial in a total of 109 patients. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline JRS Severity subscore ≥2, and a stable satisfactory therapeutic response to previous administrations of onabotulinumtoxinA (Botox). At least 10 weeks had to have elapsed since the most recent onabotulinumtoxinA administration. Patients with any significant neuromuscular disease that might interfere with the study were excluded from enrollment. Patients were randomized (2:1) to receive a single administration of XEOMIN (n=75) or placebo (n=34). Each patient in the XEOMIN group received a XEOMIN treatment (dose, volume, dilution, and injection sites per muscle) that was similar to the most recent onabotulinumtoxinA injection sessions prior to study entry. The highest dose permitted in this study was 100 Units (50 Units per eye); the mean XEOMIN dose was 33 Units per eye.

In Table 24 the most frequently injected sites, the median dose per injection site, and the median number (and range) of injection sites per eye are presented.

Table 24: Median Dose and Median Number of Injection Sites per Eye (Blepharospasm)
Injection Area	Median Units XEOMIN	Median Number of Injection Sites (Min-Max)
Temporal Area	13	2 (1 – 6)
Eyebrow Area	5	1 (1 – 4)
Upper Lid Area	10	2 (1 – 4)
Lower Lid Area	8	2 (1 – 3)
Orbital Rim	5	1 (1 – 3)

Patients were assessed during clinic visits at Weeks 3 and 6, and then by telephone or at clinic visits every two weeks up to Week 20.

The mean age of the study patients was 62 years, 65% of the patients were women, and 83% were White. The study was completed by 94% of study patients. Approximately one third of patients had other dystonic phenomena; in all but 1% this was limited to facial, cervical, perioral and mandibular muscles. No patients discontinued the study prematurely due to adverse events.

The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient's most recent value (i.e., last observation carried forward). In the ITT population, the difference between the XEOMIN group and the placebo group in the change of the JRS Severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points. Comparison of the XEOMIN group to the placebo group was statistically significant at p<0.001.

Figure 10: Frequency Distribution of Changes from Baseline JRS Severity Subscore at Week 6

Examination of age and gender subgroups did not identify substantial differences in response to XEOMIN among these subgroups.

14.5 Upper Facial Lines (Glabellar Lines, Horizontal Forehead Lines, and Lateral Canthal Lines)

Two randomized, double-blind, multi-center, placebo-controlled clinical trials, Trial 1071 (NCT04594213) and Trial 1070 (NCT04622254), were conducted to evaluate XEOMIN for use in the simultaneous intramuscular treatment of upper facial lines (GL, HFL, and LCL). Each trial included an extension period with two additional open-label treatment cycles. In these two trials a total of 730 adult subjects with GL, HFL, and LCL of at least moderate severity at maximum frown as assessed by the investigator and subject were randomized and treated.

In Trial 1071, a total of 362 subjects were randomized and treated. Of the randomized subjects, 179 subjects were treated with XEOMIN in all three treatment areas (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 92 subjects were treated with XEOMIN in the GL and HFL areas (receiving 20 U in the GL area and 20 U in HFL area), and 91 subjects were treated with placebo (receiving equal volume of placebo).

In Trial 1070, a total of 368 subjects were randomized and treated. Of the randomized subjects, 184 subjects were treated with XEOMIN in all three treatment area (receiving 64 U in total: 20 in GL, 20 U in HFL, 24 U in LCL area), 90 subjects were treated with XEOMIN in the LCL area (receiving 24 U in LCL area, 12 U per side), and 94 subjects were treated with placebo (receiving equal volume of placebo).

The mean age of the 730 treated and randomized subjects was 46.5 years. The majority of subjects were female (84%) and White (92%). Fifteen percent (15%) of subjects identified as Hispanic or Latino.

For both trials, the severity of upper facial lines (GL, HFL, and LCL) was assessed at maximum contraction using the 5-point photonumerical Merz Aesthetic Scales (MAS; 0=none, 1= mild, 2=moderate, 3=severe, 4=very severe). The MAS assessment was performed independently by both investigators and subjects. The primary timepoint was Day 30 following the first treatment.

For each upper facial area (GL, HFL, or LCL), treatment success was defined as a score of 0 (none) or 1 (mild) and at least two-grade improvement from baseline to Day 30 as rated on the corresponding scale for GL, HFL, and LCL at maximum contraction as assessed by both the investigator and the subject. The percentage of subjects with treatment success in each treatment area is presented in Table 25.

Table 25. Treatment Success at Day 30 in Adults with Upper Facial Lines (GL/HFL/LCL) in Trial 1071 and Trial 1070
	Trial 1071			Trial 1070
	XEOMIN (20 Units GL/ 20 Units HFL/ 24 Units LCL)	XEOMIN (20 Units GL/ 20 Units HFL)	Placebo	XEOMIN (20 Units GL/ 20 Units HFL/ 24 Units LCL)	XEOMIN (24 Units LCL) N=90	Placebo
	N=179		N=91			N=94
		N=92		N=184
GL	53%	53%	0%	49%	-	0%
HFL	67%	62%	0%	58%	-	0%
LCL	53%	-	0%	33%	24%	0%

Glabellar Lines

Two identically designed randomized, double-blind, multi-center, placebo controlled clinical trials (Studies GL-1 and GL-2) were conducted to evaluate XEOMIN for use in the temporary improvement of moderate to severe glabellar lines. The trials enrolled 547 healthy adult patients with glabellar lines of at least moderate severity at maximum frown. Three hundred sixty six (366) subjects were treated with 20 Units of XEOMIN and 181 subjects received placebo. Subjects were excluded if they had marked ptosis, deep dermal scarring, or an inability to lessen glabellar lines, even by physically spreading them apart. The mean age of trial subjects was 46 years. The majority of subjects were female (86% and 93% in Studies GL-1 and GL-2, respectively), and predominantly White (89% and 65% respectively). The trial subjects received either 20 Units of XEOMIN or an equal amount of placebo. The total dose was delivered in 5 equally divided intramuscular injections of 4 Units each to specific sites (see Figure 7). Subjects were followed up for 120 days.

Investigators and subjects assessed efficacy at maximum frown on Day 30 of treatment using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Composite treatment success was defined as a 2-grade improvement on this scale compared to baseline for both the investigator's and subject's assessments on Day 30. The percentage of subjects with treatment success was greater on the XEOMIN arm than the placebo arm at Day 30 in both trials (see Table 26).

Table 26: Treatment Success at Day 30 (at Least 2 Grades Improvement from Baseline at Maximum Frown) in Adults with GL in Studies GL-1 and GL-2
	GL-1		GL-2
	XEOMIN (N=184)	Placebo (N=92)	XEOMIN (N=182)	Placebo (N=89)
* Success on both the Investigator and Subject Assessments
Composite Treatment Success*	111 (60%)	0 (0%)	87 (48%)	0 (0%)
Investigator Assessment	141 (77%)	0 (0%)	129 (71%)	0 (0%)
Subject Assessment	120 (65%)	0 (0%)	101 (55%)	1 (1%)